Dr Drakaki on Paradigm-Shifting Trials in Non–Clear Cell RCC

Alexandra Drakaki, MD, PhD, associate professor, Division of Hematology-Oncology, David Geffen School of Medicine, University of California, Los Angeles, discusses key trials that have shaped the treatment paradigm in non–clear cell renal cell carcinoma (RCC).

Several trials have provided a foundation for current treatment approaches in non–clear cell RCC, Drakaki begins. One pivotal study was the phase 2 KEYNOTE-427 trial (NCT02853344), which evaluated the efficacy of single-agent pembrolizumab (Keytruda) in patients with non–clear cell RCC. The trial grouped several tumor subtypes together, including papillary, chromophobe, and unclassified RCC, Drakaki reports. Complete responses were observed in some patients treated with pembrolizumab monotherapy, showing that immunotherapy could be effective even in the non–clear cell RCC setting. This study served as proof-of-concept for the broader incorporation of immunotherapy approaches in these diverse subtypes, she explains.

Another noteworthy aspect of the KEYNOTE-427 trial was the inclusion of treatment-free survival as an end point, Drakaki says. She adds that a proportion of patients who discontinued treatment for various reasons maintained durable responses. This highlighted the potential long-term benefit of immunotherapy even after cessation of therapy, Drakaki notes.

Building on the success of KEYNOTE-427, new data have emerged supporting the combination of pembrolizumab with lenvatinib (Lenvima), Drakaki continues. The phase 2 KEYNOTE-B61 trial (NCT04704219) evaluated this combination in advanced non–clear cell RCC, following promising results from the phase 3 CLEAR trial (NCT02811861), which focused on first-line treatment for patients with clear cell RCC, she reports. Given the efficacy observed in the clear cell setting, it was logical to explore this combination in non–clear cell RCC, Drakaki emphasizes.

At the 2023 ASCO Annual Meeting, findings from KEYNOTE-B61 confirmed that most patients responded to pembrolizumab plus lenvatinib, though the median overall survival had not yet been reached at the time of publication in Lancet Oncology that same year. These results offer hope for the use of this combination in non–clear cell RCC, Drakaki concludes.